In the past two decades, cytogenetic and molecular genetic investigations have revealed that sarcomas are frequently characterized by specific chromosomal translocations, often involving genes encoding transcription factors. These translocations result in the expression of chimeric oncoproteins that contain functional domains contributed by each of the parental genes. Functioning as deregulated transcription and signaling factors, these novel proteins contribute to the malignant phenotype of the tumor cell by disrupting the tightly regulated process of target gene expression. Several therapeutic strategies that exploit the tumor-specific nature of these oncogenes are currently being investigated. These targeted approaches seek to manipulate the specific biology of these gene fusions, and along with more traditional therapeutic modalities, could augment current approaches to cancer management.